Total cavopulmonary connection is the result of a series of palliative surgical repairs performed on patients with single ventricle heart defects. The resulting anatomy has complex and unsteady hemodynamics characterized by flow mixing and flow separation. Although varying degrees of flow pulsatility have been observed in vivo, non-pulsatile (time-averaged) boundary conditions have traditionally been assumed in hemodynamic modeling, and only recently have pulsatile conditions been incorporated without completely characterizing their effect or importance. In this study, 3D numerical simulations with both pulsatile and non-pulsatile boundary conditions were performed for 24 patients with different anatomies and flow boundary conditions from Georgia Tech database. Flow structures, energy dissipation rates and pressure drops were compared under rest and simulated exercise conditions. It was found that flow pulsatility is the primary factor in determining the appropriate choice of boundary conditions, whereas the anatomic configuration and cardiac output had secondary effects. Results show that the hemodynamics can be strongly influenced by the presence of pulsatile flow. However, there was a minimum pulsatility threshold, identified by defining a weighted pulsatility index (wPI), above which the influence was significant. It was shown that when wPI < 30%, the relative error in hemodynamic predictions using time-averaged boundary conditions was less than 10% compared to pulsatile simulations. In addition, when wPI < 50, the relative error was less than 20%. A correlation was introduced to relate wPI to the relative error in predicting the flow metrics with non-pulsatile flow conditions.
Vaccination is an effective method to protect against infectious diseases. An important consideration in any vaccine formulation is the inoculum dose, i.e., amount of antigen or live attenuated pathogen that is used. Higher levels generally lead to better stimulation of the immune response but might cause more severe side effects and allow for less population coverage in the presence of vaccine shortages. Determining the optimal amount of inoculum dose is an important component of rational vaccine design. A combination of mathematical models with experimental data can help determine the impact of the inoculum dose. We illustrate the concept of using data and models to inform inoculum dose determination for vaccines, wby fitting a mathematical model to data from influenza A virus (IAV) infection of mice and human parainfluenza virus (HPIV) infection of cotton rats at different inoculum doses. We use the model to map inoculum dose to the level of immune protection and morbidity and to explore how such a framework might be used to determine an optimal inoculum dose. We show how a framework that combines mathematical models with experimental data can be used to study the impact of inoculum dose on important outcomes such as immune protection and morbidity. Our findings illustrate that the impact of inoculum dose on immune protection and morbidity can depend on the specific pathogen and that both protection and morbidity do not necessarily increase monotonically with increasing inoculum dose. Once vaccine design goals are specified with required levels of protection and acceptable levels of morbidity, our proposed framework can help in the rational design of vaccines and determination of the optimal amount of inoculum.
Background: Using a bifurcated Y-graft as the Fontan baffle is hypothesized to streamline and improve flow dynamics through the total cavopulmonary connection (TCPC). This study conducted numerical simulations to evaluate this hypothesis using postoperative data from 5 patients. Methods: Patients were imaged with cardiac magnetic resonance or computed tomography after receiving a bifurcated aorto-iliac Y-graft as their Fontan conduit. Numerical simulations were performed using in vivo flow rates, as well as 2 levels of simulated exercise. Two TCPC models were virtually created for each patient to serve as the basis for hemodynamic comparison. Comparative metrics included connection flow resistance and inferior vena caval flow distribution. Results: Results demonstrate good hemodynamic outcomes for the Y-graft options. The consistency of inferior vena caval flow distribution was improved over TCPC controls, whereas the connection resistances were generally no different from the TCPC values, except for 1 case in which there was a marked improvement under both resting and exercise conditions. Examination of the connection hemodynamics as they relate to surgical Y-graft implementation identified critical strategies and modifications that are needed to potentially realize the theoretical efficiency of such bifurcated connection designs. Conclusions: Five consecutive patients received a Y-graft connection to complete their Fontan procedure with positive hemodynamic results. Refining the surgical technique for implementation should result in further energetic improvements that may help improve long-term outcomes.
Neuromusculoskeletal models solve the basic problem of determining how the body moves under the influence of external and internal forces. Existing biomechanical modeling programs often emphasize dynamics with the goal of finding a feed-forward neural program to replicate experimental data or of estimating force contributions or individual muscles. The computation of rigid-body dynamics, muscle forces, and activation of the muscles are often performed separately. We have developed an intrinsically forward computational platform (Neuromechanic, www.neuromechanic.com) that explicitly represents the interdependencies among rigid body dynamics, frictional contact, muscle mechanics, and neural control modules. This formulation has significant advantages for optimization and forward simulation, particularly with application to neural controllers with feedback or regulatory features. Explicit inclusion of all state dependencies allows calculation of system derivatives with respect to kinematic states and muscle and neural control states, thus affording a wealth of analytical tools, including linearization, stability analyses and calculation of initial conditions for forward simulations. In this review, we describe our algorithm for generating state equations and explain how they may be used in integration, linearization, and stability analysis tools to provide structural insights into the neural control of movement.
Virtual organisms animated by a computational theory of selection by consequences responded on symmetrical and asymmetrical concurrent schedules of reinforcement. The theory instantiated Darwinian principles of selection, reproduction, and mutation such that a population of potential behaviors evolved under the selection pressure exerted by reinforcement from the environment. The virtual organisms' steady-state behavior was well described by the power function matching equation, and the parameters of the equation behaved in ways that were consistent with findings from experiments with live organisms. Together with previous research on single-alternative schedules (McDowell, 2004; McDowell & Caron, 2007) these results indicate that the equations of matching theory are emergent properties of the evolutionary dynamics of selection by consequences.
One theory of behavior dynamics instantiates the idea that behavior evolves in response to selection pressure from the environment in the form of reinforcement. This computational theory implements Darwinian principles of selection, reproduction, and mutation, which operate on a population of potential behaviors by means of a genetic algorithm. The behavior of virtual organisms animated by this theory may be studied in any experimental environment. The evolutionary theory was tested by comparing the steady-state behavior it generated on concurrent schedules to the description of steady state behavior provided by modern matching theory. Ensemble fits of modern matching theory that enforced its constant-k requirement and the parametric identities required by its equations, accounted for large proportions of data variance, left random residuals, and yielded parameter estimates with values and properties similar to those obtained in experiments with live organisms. These results indicate that the dynamics of the evolutionary theory and the statics of modern matching theory together constitute a good candidate for a mechanics of adaptive behavior.
Functional aspects of network integration in the cerebellar cortex have been studied experimentally and modeled in much detail ever since the early work by theoreticians such as Marr, Albus and Braitenberg more than 40years ago. In contrast, much less is known about cerebellar processing at the output stage, namely in the cerebellar nuclei (CN). Here, input from Purkinje cells converges to control CN neuron spiking via GABAergic inhibition, before the output from the CN reaches cerebellar targets such as the brainstem and the motor thalamus. In this article we review modeling studies that address how the CN may integrate cerebellar cortical inputs, and what kind of signals may be transmitted. Specific hypotheses in the literature contrast rate coding and temporal coding of information in the spiking output from the CN. One popular hypothesis states that post-inhibitory rebound spiking may be an important mechanism by which Purkinje cell inhibition is turned into CN output spiking, but this hypothesis remains controversial. Rate coding clearly does take place, but in what way it may be augmented by temporal codes remains to be more clearly established. Several candidate mechanisms distinct from rebound spiking are discussed, such as the significance of spike time correlations between Purkinje cell pools to determine CN spike timing, irregularity of Purkinje cell spiking as a determinant of CN firing rate, and shared brief pauses between Purkinje cell pools that may trigger individual CN spikes precisely.
by
Sarah T. Plummer;
Christoph P. Hornik;
Hamilton Baker;
Gregory A. Fleming;
Susan Foerster;
Matthew Ferguson;
Andrew C. Glatz;
Russel Hirsch;
Jeffrey P. Jacobs;
Kyong-Jin Lee;
Alan B. Lewis;
Jennifer S. Li;
Mary Martin;
Diego Porras;
Wolfgang A. K. Radtke;
John F. Rhodes;
Julie A. Vincent;
Jeffrey D. Zampi;
Kevin D. Hill
Objectives: Aortic arch reconstruction in children with single ventricle lesions may predispose to circulatory inefficiency and maladaptive physiology leading to increased myocardial workload. We sought to describe neoaortic anatomy and physiology, risk factors for abnormalities, and impact on right ventricular function in patients with single right ventricle lesions after arch reconstruction. Methods: Prestage II aortic angiograms from the Pediatric Heart Network Single Ventricle Reconstruction trial were analyzed to define arch geometry (Romanesque [normal], crenel [elongated] , or gothic [angular]), indexed neoaortic dimensions, and distensibility. Comparisons were made with 50 single-ventricle controls without prior arch reconstruction. Factors associated with ascending neoaortic dilation, reduced distensibility, and decreased ventricular function on the 14-month echocardiogram were evaluated using univariate and multivariable logistic regression. Results: Interpretable angiograms were available for 326 of 389 subjects (84%). Compared with controls, study subjects more often demonstrated abnormal arch geometry (67% vs 22%, P < .01) and had increased ascending neoaortic dilation (Z score 3.8 ± 2.2 vs 2.6 ± 2.0, P < .01) and reduced distensibility index (2.2 ± 1.9 vs 8.0 ± 3.8, P < .01). Adjusted odds of neoaortic dilation were increased in subjects with gothic arch geometry (odds ratio [OR], 3.2 vs crenel geometry, P < .01) and a right ventricle-pulmonary artery shunt (OR, 3.4 vs Blalock–Taussig shunt, P < .01) but were decreased in subjects with aortic atresia (OR, 0.7 vs stenosis, P < .01) and those with recoarctation (OR, 0.3 vs no recoarctation, P = .04). No demographic, anatomic, or surgical factors predicted reduced distensibility. Neither dilation nor distensibility predicted reduced right ventricular function. Conclusions: After Norwood surgery, the reconstructed neoaorta demonstrates abnormal anatomy and physiology. Further study is needed to evaluate the longer-term impact of these features.
This study aims to investigate the capability of smoothed particle hydrodynamics (SPH), a fully Lagrangian mesh-free method, to simulate the bulk blood flow dynamics in two realistic left ventricular (LV) models. Three dimensional geometries and motion of the LV, proximal left atrium and aortic root are extracted from cardiac magnetic resonance imaging and multi-slice computed tomography imaging data. SPH simulation results are analyzed and compared with those obtained using a traditional finite volume-based numerical method, and to in vivo phase contrast magnetic resonance imaging and echocardiography data, in terms of the large-scale blood flow phenomena usually clinically measured. A quantitative comparison of the velocity fields and global flow parameters between the in silico models and the in vivo data shows a reasonable agreement, given the inherent uncertainties and limitations in the modeling and imaging techniques. The results indicate the capability of SPH as a promising tool for predicting clinically relevant large-scale LV flow information.
BACKGROUND: Extremes of wall shear stress (WSS) have been associated with plaque progression and transformation, which has raised interest in the clinical assessment of WSS. We hypothesized that calculated coronary WSS is predicted only partially by luminal geometry and that WSS is related to plaque composition. METHODS AND RESULTS: Twenty-seven patients with coronary artery disease underwent virtual histology intravascular ultrasound and Doppler velocity measurement for computational fluid dynamics modeling for WSS calculation in each virtual histology intravascular ultrasound segment (N=3581 segments). We assessed the association of WSS with plaque burden and distribution and with plaque composition. WSS remained relatively constant across the lower 3 quartiles of plaque burden (P=0.08) but increased in the highest quartile of plaque burden (P<0.001). Segments distal to lesions or within bifurcations were more likely to have low WSS (P<0.001). However, the majority of segments distal to lesions (80%) and within bifurcations (89%) did not exhibit low WSS. After adjustment for plaque burden, there was a negative association between WSS and percent necrotic core and calcium. For every 10 dynes/cm(2) increase in WSS, percent necrotic core decreased by 17% (P=0.01), and percent dense calcium decreased by 17% (P<0.001). There was no significant association between WSS and percent of fibrous or fibrofatty plaque components (P=NS). CONCLUSIONS: IN PATIENTS WITH CORONARY ARTERY DISEASE: (1) Luminal geometry predicts calculated WSS only partially, which suggests that detailed computational techniques must be used to calculate WSS. (2) Low WSS is associated with plaque necrotic core and calcium, independent of plaque burden, which suggests a link between WSS and coronary plaque phenotype. (J Am Heart Assoc. 2012;1:e002543 doi: 10.1161/JAHA.112.002543.).